Xerostomia can be defined as the subjective sensation of dryness of the mouth. This is usually the result of a decrease in the volume of saliva secreted but may also be due to a change in composition of saliva. The most common cause for salivary gland hypofunction is drug treatment; another cause is Sjogren's syndrome.
Xerostomia is an important condition in cancer patients. In head and neck cancer patients, xerostomia arises from collateral radiation damage to the salivary glands. Xerostomia is also a problem in the broader cancer population. These patients suffer xerostomia principally as a result of the medications, e.g. cytotoxic chemotherapy agents, that they receive.
A number of pharmacological agents have been used as salivary stimulants, including yohimbine and nicotinamide. The most widely used are parasympathomimetic drugs, choline esters or anticholinesterase drugs. The most well known is pilocarpine which acts primarily on muscarinic receptors. Muscarinic agonists, when administered systemically, tend to produce side-effects including sweating and cardiovascular changes.
Bethanechol chloride, also called carbamyl-methylcholine chloride, is a known drug which has been used clinically for many years. It is available in tablets and as an injection, and is used as a stimulant of the smooth muscle of the gastrointestinal tract, and in particular the urinary bladder.
Bethanechol administered orally has been tested in the treatment of xerostomia in a small number of clinical studies. The drug has been reported to increase salivary flow. Available data suggest that effects on salivation are dose-related, up to the maximum dose which may be safely administered via the oral route. In one study in patients with head and neck cancer-associated xerostomia, it was reported that of a total of 55 patients who were considered for enrolment, 12 (22%) were not eligible to take oral bethanechol due to systemic conditions (Jham et al. 2007, Oral Oncol. 43:137-142).
One potential way to increase efficacy and yet avoid further side-effects could be to give drugs by topical application to the oral mucosa, in order to directly target the underlying minor salivary glands. For this to work the drug must be able to cross the oral mucosal membrane. The concept of buccal drug delivery is well known and a number of reviews on the subject have been published; see for example Buccal Drug Delivery by John Smart (2005), Expert Opin. Drug Deliv., 2(3):507-517. The abstract of this article states that “The buccal mucosa, however, while avoiding first pass effects is a formidable barrier to drug absorption”. And later “Currently this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa”. In general, drug permeability across buccal tissue is dependent upon physicochemical properties of the drug, such as lipophilicity, molecular weight, and degree of ionisation at physiological pH. There are two possible route of absorption through the squamous stratified epithelium of the oral mucosa, these being transcellular (intracellular, passing through the cell) and paracellular (intercellular, passing around the cell). Permeation has been reported to be mainly by the paracellular route, through the intracellular lipids produced by membrane-coating granules; however, the route taken depends upon the physicochemical properties of the drug. Generally small molecules that are predominantly lipophilic, with a Log P range of 1.6-3.3, are absorbed most rapidly, and most drugs delivered successfully via the buccal or sublingual route are lipophilic. A compound with a Log P value of less than 0 or less than 1 is usually considered too hydrophilic to be a drug candidate, particularly if it needs to cross lipophilic biological membranes for its activity.
Chemically, bethanechol chloride is a quaternary ammonium compound. It is very polar in nature and has a high aqueous solubility (hydrophilic) and a calculated log P value of around −4.0. This is one of the lowest values reported in the literature for a clinically used pharmaceutical agent. Consistent with these physicochemical properties, bethanechol does not significantly penetrate into the CNS at therapeutic doses and is only poorly absorbed from the GI tract.
WO2011/058366 (published 19 May 2011, after the priority date claimed in connection with the present specification) discloses the use, preferably in man, when administered locally to the oral mucosa, of bethanechol, e.g. as the chloride, for the treatment of xerostomia. When so administered in certain formulations, and even at doses below those known to be associated with side-effects when administered orally, bethanechol chloride is unexpectedly found to be an effective treatment of the condition. This is especially surprising, given that the physicochemical properties of bethanechol chloride are such that it is very difficult to consider using the drug for topical applications where passage of the drug across mucosal membranes would be required for activity. This is particularly the case for topical use in the treatment of xerostomia, whereby penetration of bethanechol across buccal mucosal membrane would be required for the drug to reach underlying salivary glands.